Metal complexes of 6-methoxy-1-phenazinol 5,10-dioxide (referred to hereinafter as myxin) heretofore were prepared by combining a saturated solution of myxin in a suitable organic solvent with a saturated solution of a metal salt in the same solvent. The precursor, myxin, is readily prepared by selective alkylation of iodinin (1,6-phenazindiol 5,10-dioxide).
Exemplary of the organic solvents generally employed in the prior processes used to prepare the metal complexes are acetic acid, acetonitrile, methanol, ether, chloroform, etc.
Preferably a solvent or solvent mixture in which both the myxin and the metal salts are more soluble than the metal complex formed by their reaction is used in these processes since the complex is isolated by precipitation from said solvents. This reaction may be carried out at room temperature or, to facilitate solution of the reactants and reduce the amount of solvent needed, at temperatures above room temperature.
The metal complexes of myxin have a high degree and wide spectrum of anti-microbial activity both in in vitro tests and in in vivo topical infections. In particular, the metal complexes have demonstrated a high level of activity against a wide variety of both gram positive and gram negative bacteria, fungi, protozoa and helminths. This wide spectrum of anti-microbial activity has manifested itself by the efficacy of the metal complexes as chemotherapeutic agents in combating topical infections.
There are, however, several drawbacks and deficiencies in the use of organic materials as solvents in the preparation of the metal complexes. One evident drawback is, of course, the relatively large volume of solvent which must be used. In addition, the preferred solvent, acetonitrile, is flammable and its use in conjunction with the metal complexes is hazardous. Myxin itself is highly flammable and sensitive to electrostatic discharge. Further, the metal complexes, on standing, have a tendency to form aggregates of from about 400 to about 600 microns in size after isolation and purification from these organic solvent systems. Finally, many metal complexes either cannot be prepared using organic solvents in such procedures or, if prepared, cannot be isolated therefrom by crystallization.
In the use of myxin's anti-microbial activity, a high purity material is, of course, advantageous. However, purification of myxin is expensive, difficult, time consuming and requires elaborate equipment, i.e., column chromatography.
There is thus a need for a method which overcomes these drawbacks and deficiencies. This invention provides a method for the preparation and isolation of metal complexes of myxin which eliminates the problems inherent in the use of organic solvents, and provides a non-agglomerating product in crystalline form.
In another aspect, this invention provides methods for utilizing both the ferric chloride complex and the calcium complex of myxin to purify myxin.